This AAIDCRC program proposal represents a competitive renewal of the currently funded CIRID grant. The five proposed projects employ modern molecular, genetic, and cellular technologies to try to understand the basic pathophysiology of normal and abnormal immune response. Three projects (Loh, Murphy, and Unanue) use murine while the remaining two deal directly with human material (Lublin and Chaplin). The Program goal is to elucidate the biological mechanisms that determine the outcome of an immune response by studying the genetic basis of immunity, the molecular/cellular biology of helper T cells, and the nature of non- antigen specific components that participate in the inflammatory reaction. Dr. Loh's project deals with how the CD4 molecule participates in the physiology of the helper T cell development and function by using a combination of T cell receptor transgenic, CD4 knock-out, and mutant CD4 transgenic mice. Dr. Murphy's project concentrates on the determination of helper T cell subsets by studying the transcriptional regulation of important lymphokine genes. Dr. Unanue will study the nature of macrophage activation and lymphokine production against Listeria infection using the SCID mouse model, a powerful system to dissect non-antigen specific immune response. Dr. Lublin will study the biology of the complement regulatory proteins, another important component of the non- antigen specific immune response. Dr. Chaplin will concentrate his efforts in identifying immunologically relevant genes in the HIA gene complex using reverse genetics and analysis of relevant patient populations. Finally, Dr. James Wedner and his colleagues will continue with their Demonstration and Education projects with the St. Louis asthmatic population that they have been working with for the last 4 years.